TIR signaling activates caspase-like immunity in bacteria

Area of Science:

• Microbiology
• Immunology
• Biochemistry

Background:

• Caspase proteases and Toll/interleukin-1 receptor (TIR)-domain proteins are crucial in human innate immunity and programmed cell death.
• Bacterial defense mechanisms against phages are diverse and continuously evolving.

Purpose of the Study:

• To identify and characterize a novel bacterial immune system involving caspase-like proteases and TIR-domain proteins.
• To elucidate the mechanism of action and signaling molecules employed by this bacterial defense system.

Main Methods:

• Identification and characterization of a bacterial defense system comprising a TIR-domain protein and a caspase-like protease.
• Biochemical analysis to identify the immune signaling molecule produced by the TIR protein.
• Assays to determine the activation of the caspase-like protease by the signaling molecule and its effect on phage replication.

Main Results:

• Discovery of a bacterial immune system, termed type IV Thoeris, composed of a TIR protein and a caspase-like protease.
• Identification of adenosine 5'-diphosphate-cyclo[N7:1'']-ribose (N7-cADPR) as a novel immune signaling molecule produced by the TIR protein upon phage recognition.
• Demonstration that N7-cADPR specifically activates the bacterial caspase-like protease, leading to non-specific degradation of cellular proteins and halting phage replication.
• Evidence that this TIR-caspase system is widespread in bacteria and provides efficient protection against phages.

Conclusions:

• Bacterial innate immunity employs a diverse range of TIR-produced signaling molecules.
• Regulated cell death mediated by caspase family proteases represents an ancient mechanism of innate immunity, conserved across different life forms.
• The type IV Thoeris system highlights a sophisticated bacterial defense strategy against viral predation.